Shikonin blocks human lung adenocarcinoma cell migration and invasion in the inflammatory microenvironment via the IL-6/STAT3 signaling pathway

Increasing evidence indicates that the inflammatory tumor microenvironment can lead to cancer cell metastasis. Shikonin, which is extracted from the Chinese herb Zicao (the dried root of Lithospermum erythrorhizon), possesses various pharmacological effects, but its effect on tumor metastasis in the inflammatory microenvironment remains unknown. In the present study, we aimed to investigate the potential effect of shikonin on tumor metastasis in an inflammatory microenvironment as well as the underlying molecular mechanisms. It was found that, in the inflammatory microenvironment simulated by THP-1 cell conditioned medium (THP-1-CM) in vitro, shikonin significantly inhibited the epithelial-mesenchymal transition (EMT), migration and invasion of human lung adenocarcinoma cell lines A549 and H1299. In addition, we found that interleukin-6 (IL-6), which is expressed in THP-1-CM, promoted the EMT of lung adenocarcinoma cells, and shikonin markedly inhibited IL-6-induced EMT and cell motility. Moreover, shikonin inhibited IL-6-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3), prevented phosphorylated STAT3 (p-STAT3) translocation into the nucleus, and suppressed p-STAT3 transactivation activity. Additionally, it was found that shikonin inhibited lung metastasis, EMT and expression of p-STAT3 of A549 cells in vivo. Furthermore, IL-6 levels in human lung adenocarcinoma tissues were significantly associated with tumor-node-metastasis stage and lymph node metastasis, and its expression was correlated with tumor-associated macrophage (TAM) infiltration. Together, these results suggest that shikonin suppresses the migration and invasion of human lung adenocarcinoma cells in an inflammatory microenvironment involving the IL-6/STAT3 signaling pathway.